6-halogeno-6-dehydro-3-keto-steroids



United States Patent 01 fice 3,462,425 Patented Aug. 19, 1969 ,504 Int.Cl. C07c 169/30, 169/18, 173/00 US. Cl. 260-239.55 6 Claims Thisinvention relates to steroids; and in particular to novel unsaturated6-halogeno-3-keto-steroids; and to methods of manufacturing thosecompounds.

It has been found that .a fluorine, chlorine or bromine atom in the6-position substantially improves the pharmacological activity of the 4-and 6- or the 1-, 4- and 6- positioned unsaturated keto-steroids. Thenew compounds are well tolerated by the human organism.

Accordingly, it is among the principal objects of this invention toprovide 6-halogeno-3-keto-steroids having the general formula:

H :i R1:

iii Formula I wherein R designates oxygen, (H, H) oder (H, 0R 0a or [i];R designates oxygen,

0R4 0 0 \OR4 or R designates H, or lower acyl; R designates hydrogen, oracyl; R designates acetyl-, CH -CECH or CO-CH OR R designates acetyl orOR;,; and X designates a halogen atom having an atomic number notexceeding 35, i.e., fluorine, chlorine or bromine;

Formula II wherein R and R have the significance as defined in Formula I(including the corresponding compounds also having a double bond in the1,2-position), into the corresponding 6-halogeno-7-hydroxy-steroids; andthen converting the 6-halogeno-7-hydroxy-steroids by reacting them witha dehydrating agent into doubly or triply unsaturated6-halogeno-3-keto-steroids of the general Formula I.

The conversion of compounds of the Formula II to the6-halogeno-7-hydroxy-steroids may be achieved by treatment of thestarting material with a per acid followed by treatment with a hydrogenhalide.

The compounds of the Formula I may, optionally, be treated withsaponifying agents and/or, optionally, converted into physiologicallysafe 2l-esters.

According to the invention, it is not necessary to isolate the6-halogeno-7-hydroxy-steroid which is obtained as an intermediateproduct. ()ne can convert the raw solution thereof as formed directlyinto the final product simply by allowing it to stand at roomtemperature for about 4 to 24 hours in the presence of an acid. In mostcases the acid which is present in the solution as a result of thepreparation of the halogen hydrin compound is suflicient to effectsplitting off of the water.

The 6-halogeno-7-hydroxy-steroids are prepared from the corresponding6-dehydrosteroids through the 6a,7aeporddes. The 6-dehydrosteroids arepreferably left standing in chlorinated hydrocarbons, such as chloroformor methylene chloride, for a prolonged period of time withmonoperphthalic acid. The subsequent rupture of the epoxide ring with ahydrogen halogenide is elfected when hydrogen chloride or hydrogenbromide are used, preferably in solvents, such as the lower carbonic(carboxylic) acids, chloroform or dioxane. The reaction mixture is leftstanding for several hours, to which preferably small quantities ofwater may be added. For the rupture of the epoxide ring with hydrogenfluoride, working is preferably effected in solvents, such as chloroformor methylene chloride in the presence of Lewis bases, as for example,tetrahydrofurane, by letting the solution stand for several days with alarge excess of hydrogen fluoride.

If the 6-halogeno-7-hydroxy-steroids are isolated and are obtained asintermediate products, practically all the usual agents which split olfwater are useful for the subsequent dehydration. For example, thetreatment with p-toluene sulfonic acid, thionyl chloride orphosphorusoxy chloride in a tertiary base, for example in pyridine,results in good yields of the compounds of the general Formula I above.

In most cases it is sufiicient for splitting off of water to add astronger acid, as for example HBr in glacial acetic acid at roomtemperature. Good yields can also be obtained with p-toluene sulfonicacid in toluene at boiling temperature.

In the preparation of the 1,4,6-trien-steroids according to thisinvention, the introduction of the 1,2-positioned double bond may beeflected as well after the dehydration of the corresponding6-halogeno-7a-hydroxy-steroid. A suitable agent for such adehydrogenation is, for example SeO The preferred starting materials arethe following compounds:

6-dehydrocortisone-2 l-acetate, 6-dehydro-hydrocortisone-triacetate,6-dehydro-1l-epihydrocortisone-l1,21-diacetate,6-dehydro-Reichsteins-substance-S-Z l-acetate, 6-dehydro-prednisone-2l-acetate, 6-dehydro prednisolone-triacetate,

6-dehydro-1 l-epi-prednisolone-2 l-diacetate,

or 1,6-bis-dehydro-Reichsteins-substance-S-2l-acetate.

However, in the 6- or the 1- and 6-position unsaturated derivatives ofprogesterone, 17a-methyl-testosterone, c-

ethinyl-testosterone or the 17-e'ther or the ester of the testosteronecan also be used as starting material. The 6- or 1- and 6-positionunsaturated derivatives of androstenedione are also suitable startingmaterials for preparing the 6-halogeno-steroids according to theinvention.

The compounds of the general Formula II which contain double bonds inthe 4- and 6-p0sition and are employed as starting materials, can beobtained, for instance, by dehydrogenating the corresponding4-en-3-ketosteroids (A -3-keto-steroids) with chloranil. The triplyunsaturated compounds of the Formula II are obtained, for instance, bydehydrogenating the basic 4,6-diene-3- keto-steroids with chemical ormicrobiological dehydrogenation agents, as for example SeO or Bacillussphacricus.

If Y the compounds of the general Formula I contain ester groups, suchgroups can be converted in a known manner into the free hydroxyl groups,as for example by the action of acidic or alkaline saponificationagents. Preferably, aqueous sodium hydrogen carbonate solution is usedwith methanol added thereto. The saponification of the triacetate of the6-halogeno-6-dehydro-prednisolone and the 6-halogeno-6-dehydro-cortisolis preferably effected microbiologically, for example, by the action ofthe microorganism Flavobacterium dehydrogenans.

If the compounds, prepared in accordance with the inventino, contain a21-hydroxyl group, they can be converted into physiologicallyunobjectionable esters, for instance, with the following acids or thederivatives thereof suitable for esterification (for example, acidchlorides or anhydrides): acetic acid and the higher homologues thereof;succinic acid and the higher homologues thereof; aminooralkylamino-carbonic (carboxylic) acids; amino-dicarbonic (dicarboxylic)acids; tetrahydrophthalic acid; cyclopentylpropionic acid; phosphoricacid; sulfuric acid, etc.

The new compounds are pharmacologically well tolerated and are useful asdrugs. The 6-halogeno-6-dehydroderivatives of prednisone andprednisolone and those of cortisone and cortisol excel inanti-inflammatory (antiphlogistic) activity and show good tolerance. The6-halogeno-6-dehydro-progesterone derivatives are strong progestationalagents, whereas the 6-halogeno-6-dehydro-testosterone derivatives areexcellent anabolics.

The following are examples in accordance with the invention.Temperatures are given in degrees centigrade. The symbol g. designatesgram.

EXAMPLE 1 (a) 70 g. of 6-dehydrocortisone-2l-acetate are dissolved in 7liters of absolute chlorolorm, mixed with 26.7 g. of monoperphthalicacid and left standing for 60 hours at room temperature. Then thereaction mixture is successively shaken with sodium bicarbonatesolution, water, iron (ID-sulfate solution and again with water, driedand concentrated. The 60:, 7a-epoxy-cortisone-21- acetate crystallizesfrom acetone. F.P. 267-269.

In a similar manner, sometimes using methylene chloride as solvent andsometimes using only 20% of the solvent given in the example above, thefollowing compounds can be produced:

(b) 6a,7a-epoxy-cortisol-2l-acetate, F.P. 267-270"; (cc) =+155(dioxane); A 240 m E 1% 375.

(c) 6a,7u-epoxy-prednisone-2 l-acetate, F.P. 266-270"; (u) =+156(dioxane); A 240 mu, E 1% 375.

(d) 6a,7ot-epoxy-17a-acetoxyprogesterone, F.P. 253- 255; A 241 m E 1%394; (a) =+19 (dioxane).

(e) 6a,7a-epoxy-prednisolone-2l-acetate, F.P. 254- 260; (u) =-}64.0(dioxane), A 244 III/L, E 1% 387.

(f) 6a,7u-epoxy-progesterone, F.P. 178-180, A 240 me, E 1% 450; (a)==-|-134 (dioxane).

(g) 6w,7a-epoxy-testosteronpropionate, F.P. 118, x 241 mg, E 1% 427; (a)=+47 (dioxane).

(h) 6a,7a-epoxy, 17a-ethinyl-testosterone, F.P. 288- 289, A 241 me, E 1%466; (a) =-33 (dioxane).

(i) 6a,7a epoxy-Reichsteins substance-S-Zl-acetate,

4 F.P. 235-238; Am, 240 III/1., E 1% 400; (a) ="-{-57.8 (dioxane).

(k) 6u,7ot epoxy-1l-epi cortisol-l1,21-diacetate, F.P. 208210; (a) =-+78(dioxane); A 240 III/.4, E 1% 325.

(l) 6a,7a-epoxy-17oc-methyl -testosterone, F.P. 197- l99; )t 240 my, E1% 454; (a) =+28 (dioxane).

(m) 6a,7a-epoxy-1l-epi-cortisol-l l-tosylate-Zl-acetate.

(n) 6a,7a-epoxy-cortisol-triacetate.

(o) 6a,7u-epoxy-prednisolone-triacetate.

The compounds named under (in) to (0) above were used as raw productsfor the following reactions.

EXAMPLE 2 (a) To a solution of 10 g. of 6a,7u-epoxy-cortisone-2l-acetate in 260 cc. of absolute chloroform cooled to 60 are added 100cc. of a solution of 35 g. of H 1 in tetrahydrofuran/chloroform (2:1)also cooled to 60 C.; and the mixture is left standing for 65 hours atroom temperature. Then the reaction mixture is poured into a sodiumbicarbonate solution (saturated), shaken up with acetic ester(ethylacetate) and worked up as usual. The crystalline raw product isfiltered with acetic ester (ethyl acetate) over silica gel. The6fl-fluoro-7uhydroxy-cortisone-Zl-acetate has a melting point of 253-261.

Analogously to this example, the following compounds can be prepared:

(b) 6B-fluoro-7a-hydroxy-prednisone-2l-acetate, F.P. 285-288.

(c) fl-fluoro-7ot-hydroxy-progesterone, F.P. 219-222". A 231 m E 1% 340;(a) =+56 (dioxane).

(d) 6,8-fiuoro7a-hydroxy 17a acetoxy-progesterone, F.P. 228-230, x 232 mE 1% 306; (a) '=-28.9 (dioxane).

(e) 6/3-fiuoro-7u-hydroxy-testosterone 17-propionate; F.P. 169-171", A232 my, E 1% 327; (a) =11 (dioxane).

(f) 6,8-fiuor0-7ot hydroxy 17oz ethinyl-testosterone, A 233 m E 1% 349;F.P. 234-236; (a) =-70.6 (dioxane).

(g) 6fi-fiuoro 7oz hydroxy-Reichsteins-substance-S- 21-acetate, F.P.248-249, 7. 232 Ill/1,, E 1% 297; (a) =+4O (dioxane).

(h) 6fi-fluoro-7u-hydroxy 11 epi cortisol 11,21- diacetate.

(i) 6p-fluoro-7a-hydroxy-ll-epi-cortisol 11 tosylate- 21-acetate.

(k) 6 3-fluoro-7a-hydroxy-cortisol-11fi,17a,21-triacetate.

acetate.

The compounds named under (h) to (1) above were used as raw products forthe following reactions.

EXAMPLE 3 (a) 1.9 g. of 6fi-fluoro-7a-hydroxy-cortisone-2l-acetate aredissolved in 25 cc. of acetic acid and left standing together with 5 g.of hydrogen bromide/glacial acetic acid for 1 hour at room temperature.Thenthe reaction mixture is poured into water, the crystalline productis sucked off, washed and recrystallized from acetone. The pure6-fluoro-6-dehydro-cortisone-2I-acetate melts at 230- 232 C., E 1% at280 my 537, (u) (dioxane).

heated together with 700 cc. of p-toluene-sulfonic acidin 70 cc. ofabsolute toluene for 60 minutes while being refluxed. Then the reactionmixture is diluted with ether (diethylether), shaken out with a sodiumbicarbonate solution, dried and concentrated. The6-fiuoro-6-dehydroprogesterone crystallizes out from acetate with amelting point of 208-209", x 283 mu, E 1% 642.

(c) Analogously to Example 8(b), the6-fluoro-6-dehydro-17a-acetoxy-progesterone can be obtained. F.P.235236, x 283 me, E 1% 671; (a) =65.7 (dioxane).

Analogously to Example 8(a), the following compounds can be obtainedwhich can be saponified by treatment with sodium hydrogen carbonate:

((1) 6-fluoro 6 dehydro-testosterone-propionate, F.P. 124-125, x 282 m E1% 672; (a) =42.6 (dioxane).

(e) 6-fiuoro-6-dehydro-prednisone 21 acetate, RP. 239-241", (t) =|156(dioxane), A 224, 256, 294 mp, E1% 262, 288, 278.

6-fiuoro-6-dehydro-prednisone, F.P. 214-216, A 224, 255, 293 mm, B 1%273, 296, 285; (or) =+122.6 (dioxane).

(f) 6-fluoro-6-dehydro-17a-ethinyl-testosterone, 242-245", A 283 m E 1%475.

(g) 6-fiuoro 6 dehydro-Reichsteins-substance-S-21- acetate, F.P.197-200", k 283 my, E 1% 536; (u) =+106 (dioxane).

6-fluoro-6-dehydro-Reichsteins-substance-S, F.P. 202- 204, (oz) '=+28.1,A 283 me, E 1% 663.

(h) 6-flu0r0-6-dehydro 11 epi-cortisol 11,21 diacetate, F.P. 240-243", A283 mu, E 1% 440.

6-fiuoro-6-dehydro-1l-epi-cortisol F.P. ZZZ-224, A 284 III/1., E 1% 644;(oc) =8 (dioxane).

(i) 6-fluoro-6-dehydro-1l-epi-cortisol-ll-tosylate 21- acetate, F.P.163-166, x 226, 281 Ill/1.,E 1% 284,401.

(k) 6-fluoro-6-dehydro-cortisol-triacetate, (used as raw product for thefollowing reaction).

Microbiological saponification: A sterilized nutrient solutionconsisting of 80 g. of glucose, 50 g. of yeast extract, 30 g. ofammonium chloride plus water to make a total of 10 liters and butteredto a pH of 7.0 with l/30 molar phosphate buffer solution according toSorensen, is inoculated with 200 ml. of a shaking culture ofFlavobacterium dehydrogenans. While being stirred and aerated, theculture is left to grow at 28 C. for 12 hours. Then a concentratedsolution of 12 g. of 6-fluoro-6-dehydro-cortisol-triacetate indimethylformamide is added and stirred for a further 12 hours at 28while being aerated. The fermentation solution is extracted 3 times,each time with liters of chloroform. The extract is dried andconcentrated. The 6-fluoro-6-dehydro-cortisol crystallizes out from theresidue after filtration over silica gel.

(l) 6 fluoro 6 dehydro-prednisolone-triacetate. The saponification to6-fluoro-6-dehydro-prednisolone is effected analogously to Example 3(k).

From the 2l-hydroxysteroids the following physiologically safe 21-esterswere prepared:6-fiuoro-6-dehydro-cortisone-21-diethylamino-acetate-hydrochloride, 6fluoro-6- dehydro-cortisone-Zl-hemisuccinate, 6fluoro-6-dehydrocortisol-2l-hemisuccinate, 6 fluoro-6-dehydro-prednison-21-diethyl-amino-ac(state-hydrochloride, 6fiuoro-6-dehydro-prednisolone-Zl-hemisuccinate, 6-fluoro 6 dehydro--prednisolone-diethyl-amino-acetate-hydrochloride.

EXAMPLE 4 5 g. of 6-fluoro-6-dehydro cortisone 21 acetate are boiledunder reflux for 48 hours with 250 cc. of tertiary butanol, 3 g. ofselenium dioxide and 2.5 cc. of acetic acid. The precipitated seleniumis sucked oif and the solution is concentrated by evaporation. The6-fluoro-6-dehydro-prednisone-Zl-acetate is obtained in severalcrystalline fractions. Upon filtration over silica gel the pure productmelts at 239-241 In an analogous manner the 6-fluoro-6-dehydro-cortisol-triacetate can be converted to 6-fiuoro-6- ReferencesCited UNITED STATES PATENTS 3/1956 Colton 260-23955 OTHER REFERENCESFarmaco Ed. Sci, vol. 13 (1958), pages 52-63, article by Camerino etal., Chem. Abstracts, vol. 52, paragraphs 13,7680).

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

4. 6A,7AA-EPOXY-17A-ACETOXYPROGESTERONE.